JP2007506709A - Benzimidazolone and quinazolinone derivatives as agonists for the human ORL1 receptor - Google Patents

Abstract

の化合物に関する。The present invention relates to a group of novel benzimidazolone and quinazolinone derivatives that are agonists for the human ORL1 (nociceptin) receptor. The present invention also relates to the manufacture of these compounds, pharmaceutical compositions containing pharmacologically effective amounts of at least one of these imidazolone and quinazolinone derivatives as active ingredients, and the treatment of disorders involving the ORL1 receptor. For the use of these pharmaceutical compositions. The present invention relates to general formula (1) wherein the symbols have the meanings indicated in the description:
[Chemical 1]

Of the compound.

Description

  The present invention relates to a group of novel benzimidazolone and quinazolinone derivatives that are agonists for the human ORL1 (nociceptin) receptor. The present invention also provides for the preparation of these compounds, pharmaceutical compositions containing a pharmaceutically effective amount of at least one of these imidazolone and quinazolinone derivatives as active ingredients, and the treatment of disorders involving the ORL1 receptor. For the use of these pharmaceutical compositions.

  The present invention relates to the use of the compounds disclosed herein for the manufacture of a medicament that provides a beneficial effect. Beneficial effects are disclosed herein or will be apparent to those skilled in the art from the specification and general knowledge in the art. The invention also relates to the use of a compound of the invention for the manufacture of a medicament for treating or preventing a disease or condition. More particularly, the present invention relates to novel uses for the treatment of diseases or conditions disclosed herein or apparent to those skilled in the art from the specification and general knowledge in the art. In aspects of the invention, certain compounds disclosed herein are used in the manufacture of a medicament.

  The 'Opioid Receptor-Like 1 (opioid receptor-like 1)' receptor was identified from a human cDNA library. This “orphan receptor” was proved to have close homology with μ-, κ- and δ-opioid receptors (see Non-Patent Documents 1 and 2). Despite its close sequence and structural similarities to the opioid receptor, classical opioid receptor ligands do not interact with the ORL1 receptor. In 1995, a 17-amino acid neuropeptide was purified from brain extracts and subsequently shown to be a natural ligand for the G protein-coupled ORL1 receptor (see Non-Patent Documents 3 and 4). This peptide was named orphan FQ or nociceptin. It does not bind to the three traditional opioid receptors. These findings triggered a substantial study of the functional role of the ORL1 receptor and novel ligands for it.

  This has resulted in hundreds of publications including several reviews describing both peptide and non-peptide ligands (see, eg, Non-Patent Document 5) and numerous patent applications. The compounds described differ significantly in potency and further selectivity (ORL1 for μ-opiate receptors) for the ORL1 receptor. Since μ-opiate receptors are widely distributed throughout the body, lack of selectivity can lead to a series of undesirable opiate-like side effects (eg, sedation, respiratory depression, tolerance and dependence) ( Non-patent document 6). The in vivo pharmacological and pharmacokinetic properties of the described compounds are also significantly different.

A number of ORL1-related patent applications, for example, Patent Documents 1-6, relate to benzimidazolone derivatives (see Patent Documents 1-6). Of the latter, Patent Document 5 is closest to the present invention. However, the benzimidazolone derivatives described therein do not appear to meet the generally accepted criteria for being useful for useful therapeutic agents. They have the following features:
(1) moderate potency (affinity for ORL1 receptor in the range of 166-1252 nM), (2) low selectivity for μ-opiate receptor (affinity in the range of 19-457 nM),
(3) no evidence of availability after oral administration, and (4) no evidence of CNS availability.
Have

The most potent ORL1 agonist described is Ro 64-6198. This compound does not contain a benzimidazolone moiety, but instead has a spiro core (see Patent Document 7, Non-Patent Documents 7 and 8). Ro 64-6198 is mentioned to be a potent and selective compound that readily penetrates the “blood brain barrier”. However, despite its favorable in vitro binding data, the in vivo profile of this ligand has several drawbacks:
(1) less effective in anxiety models than predicted based on in vivo data;
(2) The therapeutic window between the desired effect as an ORL1 agonist and the adverse opiate side effects in vivo is less than expected based on in vitro data;
Indicates.

The teachings on benzimidazolone derivatives and Ro 64-6198 cited above do not indicate a direction on how to improve the in vivo pharmacological profile of the best compounds described. In a review of the subject matter ("Characterization of opiates, neurologicals, and synthetic analogs at ORL1 and opioid receptors", non-patent description of opiates, neurostabilizers and synthetic analogues in ORL1 and opioid receptors). Zaveri et al., "The ORL1 receptor ligand, even in the absence of a model of the small molecule in the active site or the crystal structure of the ORL1 receptor bound to the small molecule, has a very close structural similarity. We must be very careful when assessing SAR between different groups ”(see Non-Patent Document 9).
International Publication No. 98/54168 Pamphlet WO99 / 36421 pamphlet International Publication No. 00/006545 Pamphlet International Publication No. 00/08013 Pamphlet International Publication No. 01/39775 Pamphlet US2002020128288 specification European Patent No. 0856514 Molleau et al., FEBS Lett. , 341, 33-38, 1994 Bunzow et al., FEBS Lett. , 347, 284-288, 1994. Reinscheid et al., Science, 270, 792-794, 1995 Meunier et al., Nature, 377, 532-535, 1995. Grond et al., Anaesthest. 51,996-9005, 2002 Drug News Perspect. , 14, 335, 2001 Eur. J. et al. Med. Chem. , 35 (2000) 839-851 Proc. Natl. Acad. Sci. USA. 2000, 97, 4938 Eur. J. et al. Pharmacol, 428, 29-36, 2001.

Surprisingly, it has now been shown that in a series of benzimidazolone and quinazolinone derivatives with a novel combination of substituents, a group of compounds has a high affinity for the human ORL1 receptor. I found it. Furthermore, these compounds show excellent selectivity for the ORL1 receptor relative to the μ-opiate receptor, are readily available after oral administration, and cross the brain blood barrier. The in vitro and in vivo pharmacological profiles of some of these compounds are more than those of Ro 64-6198, especially regarding the therapeutic window between the desired potency as an ORL1 agonist and the side effects of undesirable opiate in vivo. Are better. The present invention relates to a general formula (1)

[Where:
R ₁ represents H, alkyl (1-6C), alkyl (1-3C) cycloalkyl (3-6C), carboalkoxy (2-7C) or acyl (2-7C);
_{[] M} is - _{(CH 2) m} - represents, wherein m is either 0 or 1,
R ₂ is halogen, CF ₃ , alkyl (1-6C), alkyl (1-3C) cycloalkyl (3-6C), phenyl, amino, aminoalkyl (1-3C), alkyl (1-3C) amino, dialkyl (1-3C) amino, cyano, cyanoalkyl (1-3C), hydroxy, hydroxyalkyl (1-3C), (1-3C) alkoxy, OCF ₃ , acyl (2-7C), trifluoroacetyl, aminocarboxyl , (1-3C) alkylsulfonyl or trifluoromethylsulfonyl, and n is an integer of 0 to 4, provided that when n is 2, 3 or 4, the R ₂ substituents are the same Or it may be different,
A is a saturated or partially unsaturated ring;
_{[] O} and _{[] p} are each - _{(CH 2) o} - and - _{(CH 2) p} - and represents, wherein A is a ring of partially unsaturated, and o and p are independently 0, 1 or The meaning of -CH- is also possible when
R ₃ , R ₄ , R ₅ and R ₆ independently represent hydrogen, alkyl (1-3C), alkyl (1-3C) cycloalkyl (3-6C), CH ₂ OH or (R ₃ and R ₅ ) Or (R ₃ and R ₆ ) or (R ₄ and R ₅ ) or (R ₄ and R ₆ ) can form an alkylene bridge of 1 to 3 carbon atoms, provided that o When R is 2, R ₃ is hydrogen, and when p is 2, R ₅ is hydrogen;
R ₇ is H, halogen, CF ₃ , alkyl (1-6C), alkyl (1-3C) cycloalkyl (3-6C), amino, aminoalkyl (1-3C), alkyl (1-3C) amino, dialkyl (1-3C) represents amino, hydroxy, hydroxyalkyl (1-3C), (1-3C) alkoxy, OCF3, acyl (2-7C), aminocarboxyl or (1-3C) alkylsulfonyl]
And pharmacologically acceptable salts and prodrugs thereof.

All compounds having the formula (1), racemates, mixtures of diastereomers and individual stereoisomers belong to the invention. Accordingly, compounds where the substituent on a carbon atom that may be asymmetric is in either the R-configuration or the S-configuration belong to the present invention. Furthermore, prodrugs, ie compounds which are metabolized to a compound having formula (1) when administered to a human by any known route belong to the present invention. Prodrugs are bioreversible derivatives of drug molecules that are used to overcome any obstacles to the utilization of the parent drug molecule. These disorders include, but are not limited to, solubility, permeability, stability, pre-systemic metabolism and targeting limitations (J. Stella, “Prodrugs as therapeutics”, Expert Opin. Ther. Patents. , 14 (3), 277-280, 2004). In particular, this relates to compounds having primary or secondary amino or hydroxy groups. Such compounds react with organic acids and are easily removed after administration, such as, but not limited to, amidines, enamines, Mannich bases, hydroxyl-methylene derivatives, O- (acyloxymethylene. Carbamate) derivatives, carbamates, esters, amides or enaminones can be used to produce compounds having formula (1). Prodrugs are inactive compounds that are converted to the active form upon absorption (Medicine Chemistry: Principles and Practice, 1994, ISBN 0-85186-464-5, Ed .: FD King, p. 216. ).

In particular, the present invention provides that A is a saturated ring, R ₁ represents hydrogen, alkyl (1-3C) or acyl (2-4C), R ₃ , R ₄ , R ₅ and R ₆ are independently hydrogen, alkyl or or represents (1-3C) _{(R 3} and _{R 5),} or _{(R 3} and _{R 6)} or 1-3 _{(R 4} and _{R 5),} or _{(R 4} and _{R 6)} together When o is 2, R ₃ is hydrogen, and when p is 2, R ₅ is hydrogen and R ₇ is H. , halogen, CF _3, alkyl (l-3C), amino, aminoalkyl (l-3C), alkyl (l-3C) amino, dialkyl (l-3C) - amino, hydroxy, (l-3C) alkoxy or OCF ₃ represents and _R 2, m, n, o and p are shown in the It relates to compounds having formula (1) with the taste.

More particularly, the present invention provides that A is a saturated ring, m = 0, n = 0 or 1, o = 1, p = 1, R ₁ = H or acetyl, R ₂ is halogen, CF ₃ , alkyl (1-3C), amino, cyano, OCH ₃ or OCF ₃ and R ₃ , R ₄ , R ₅ and R ₆ independently represent hydrogen or alkyl (1-2C) or (R ₄ and R ₆ ) Together can form an alkylene bridge of 1 to 2 carbon atoms and R ₇ is H, halogen, CF ₃ , alkyl (1-3C), amino, hydroxy or OCF ₃ It relates to the compound of (1).

  Even more preferred are compounds having formula (2) and stereoisomers thereof. Hereinafter, this compound is referred to as “Example 1”.

  The compounds of the invention can be brought into a form suitable for administration by conventional methods using auxiliary substances and / or liquid or solid carrier substances.

  Pharmaceutically acceptable salts can be obtained using standard methods well known in the art, for example by mixing the compounds of the invention with the appropriate acid. Suitable acid addition salts can be formed with inorganic acids such as hydrochloric acid or organic acids such as fumaric acid.

The compounds of the invention of general formula (1) and their salts have ORL1 agonist activity.
They are useful for the treatment of disorders that involve the ORL1 receptor or can be treated by manipulation of these receptors. For example, acute and chronic pain conditions, central nervous system disorders, particularly but not limited to improving symptoms of anxiety and stress disorders, depression, various forms of epilepsy, stroke, cognitive and memory deficits Characteristic disorders such as Alzheimer's disease, Kreutzert-Jakob disease, Huntington's disease, Parkinson's disease, neurological rehabilitation (post traumatic brain injury); acute brain or spinal cord injury, substances (such as addiction and abuse) Substance-related disorders, including use disorders and substance-induced disorders (such as substance withdrawal symptoms); eating disorders such as anorexia nervosa and bulimia nervosa, obesity; gastrointestinal disorders, especially irritable bowel syndrome, inflammation Renal disease characterized by an inflammatory bowel disease (Crohn's disease) and ulcerative colitis, urinary tract inflammation, water retention / excretion or salt excretion; cardiovascular disorders such as Muscle infarction, arrhythmia, hypertension, thrombosis, anemia, arteriosclerosis, angina, skin diseases such as urticaria, lupus erythematosus and pruritus; ophthalmic disorders such as glaucoma; chronic obstructive pulmonary disease, bronchi Useful for treatment in respiratory disorders including inflammation and cystic fibrosis; diseases of the immune system, and viral infections.

  The compounds of the present invention are generally administered as a pharmaceutical composition which is an important and novel aspect of the present invention due to the presence of the compounds, more particularly the specific compounds disclosed herein. The types of pharmaceutical compositions that can be used include, but are not limited to, tablets, chewable tablets, capsules, solutions, parenteral solutions, suppositories, suspensions, and those disclosed herein, or Other types apparent to those skilled in the art from the specification and general knowledge in the technical field are included. In an embodiment of the present invention, there is provided a pharmaceutical pack or kit comprising one or more containers filled with one or more ingredients of the pharmaceutical composition of the present invention. Such one or more containers may contain various document materials, such as instructions for use or the manufacture and use of pharmaceuticals whose information reflects their manufacture, use or marketing authorization for human or livestock administration. Alternatively, information in a form described by a government agency that controls sales can be attached.

General aspect of synthesis The compounds of the invention and their salts can be obtained according to the general route outlined below in Scheme 1:

The starting compound for this general pathway is obtained as follows:
Benzimidazolone [(i), when m = 0] is J. Med. Chem. , 30 , 814-819, 1987 and WO 99/36421 pamphlet. Quinazolinone [(i), when m = 1] is Chem. Phar. Bull. , 33 . 1116-1128, 1985. The N-nitro-oxime (ii) of (substituted) 2,3,3a, 4,5,6-hexahydro-1H-phenalen-1-one is prepared from the corresponding ketone. These ketones are sequentially described in Eur. J. et. Med. Chem. . 35 , 839-851, 2000, prepared from the corresponding (substituted) tetralone.

Specific examples of synthesis
Synthesis of Example 1:
A detailed overview of the synthesis of Example 1 is given in Scheme 2.

The first four steps from Scheme 2 are Eur. J. et. Med. Chem. . 35 , 839-851, 2000. Starting with intermediate compound 5 ^* (see scheme 2), the synthesis is as follows:

Step 5 (Scheme 2): 2,3,3a, 4,5,6-hexahydro-1H-phenalen-1-one (compound 5 ^* ) 52 g (0.28 mol), hydroxylamine. 28.1 g (0.40 mol) of HCl and sodium acetate. A mixture of 55 g (0.40 mol) of 3H ₂ O (in 500 ml of 96% ethanol) was stirred at 80 ° C. for 4 hours and at room temperature for a further 16 hours. The resulting mixture was concentrated under vacuum and 750 ml of dichloromethane and 300 ml of a 5% aqueous solution of NaHCO ₃ were added. The aqueous layer was washed twice with 100 ml dichloromethane and the combined organic layers were washed with 100 ml saline, dried over MgSO ₄ and concentrated in vacuo.

Step 6 (Scheme 2): The resulting off-white solid oxime (compound 6 ^* ) 58.8 g (representing quantitative yield) was suspended in 600 ml of t-butyl methyl ether. At room temperature, 230 ml of an aqueous solution of 41.4 g (0.6 mol) of sodium nitrate were added to this suspension, followed by 290 ml of 2N sulfuric acid solution. After stirring at 40 ° C. for 16 hours, the mixture was cooled to room temperature and 300 ml of a saturated aqueous NaHCO ₃ solution was added. The aqueous layer was extracted twice with 300 ml of t-butyl methyl ether and the combined organic layers were washed with 150 ml of saline, dried over MgSO ₄ and concentrated in vacuo. The resulting brown oil was purified by column chromatography (silica gel) using dichloromethane as eluent. The oily product obtained after concentration under vacuum was triturated with cyclohexane and the resulting precipitate was collected by filtration and dried. Pure NO ₂ - was obtained imine (compound ^{7 *)} as an off-white solid having a melting point of 64 to 69 ° C. (34g, 0.148 mol, 52% yield).

Step 7 (Scheme 2): 6.51 g (30 mmol) 4- (1-benzimidazolone) piperidine (compound 8 ^* , ACROS), 6.9 g (30 mmol) NO ₂ -imine (compound 7 ^* ) and di A mixture of 5.25 ml of isopropylethylamine (in 450 ml of 1,2-dichloro-ethane) was heated to 50 ° C. and stirred for 16 hours under N ₂ . After cooling to room temperature, 12.7 g (60 mmol) of NaBH (OAc) ₃ was added and the resulting mixture was stirred at room temperature under N ₂ for 24 hours. After concentration of the reaction mixture under vacuum, 500 ml dichloromethane and 500 ml NaHCO ₃ 5% aqueous solution were added with stirring. The aqueous layer was washed twice with 100 ml dichloromethane and the combined organic layers were washed with 100 ml saline, dried over MgSO ₄ and concentrated in vacuo. The crude product was purified by column chromatography (silica gel) with a mixture of dichloromethane-methanol-ammonia (92: 7.5: 0.5) as eluent. Concentration in vacuo gave the pure product (8.09 g, 21 mmol, 70% yield, mp 155-158 ° C.). To 8.09 g (21 mmol) of pure product was added 60 ml of ethanol and 2.44 g (21 mmol) of fumaric acid. Concentration of the resulting solution in vacuo afforded the fumarate salt of Example 1 (10.53 g, 21 mmol, quantitative yield) as a white foam with a M ⁺ of 358 m / z and a melting point of 232-234 ° C. It was.

Synthesis of Example 2 :
A mixture of 2.31 g (10 mmol) of 4- (1-quinazolinone) piperidine and 2.3 g (10 mmol) of NO ₂ -imine (compound 7 ^* ) under nitrogen was heated (in 100 ml of 1,2-dichloroethane). The mixture was stirred at 50 ° C. for 7 hours and at room temperature for 16 hours. Then 4.2 g (20 mmol) NaBH (OAc) ₃ was added and the resulting mixture was stirred at room temperature under N ₂ for 24 hours. After the reaction mixture was concentrated in vacuo, 200 ml of dichloromethane and 200 ml of 5% aqueous NaHCO ₃ solution were added with stirring. The aqueous layer was washed twice with 40 ml dichloromethane and the combined organic layers were washed with 40 ml saline, dried over MgSO ₄ and concentrated in vacuo. The crude product was purified by column chromatography (silica gel) with a mixture of dichloromethane: methanol: ammonia (94.5: 5: 0.5) as eluent. The pure product (2.5 g, 6.2 mmol) produced after concentration in vacuo was dissolved in 50 ml of HCl in ethanol. Concentration in vacuo gave the HCl salt of Example 2 (2.05 g, 4.7 mmol, 47% yield) as a white amorphous solid with M ^{+ of} 402 m / z and a melting point of 172 ° -180 ° C. .

Synthesis of Example 13:
A detailed overview of the synthesis of Example 13 is given in Scheme 3:

Step 1 (Scheme 3): 2.84 g (20 mmol) of 2,4-dichloronitrobenzene (compound 9 ^* , Aldrich), 4.1 ml (20 mmol) of 4-amino-1-benzylpiperidine (compound 10 ^* , Aldrich) , A solution of 4.46 g (32 mmol) of K ₂ CO ₃ (in 50 ml of dimethylformamide) was stirred at 95 ° C. for 18 hours under N ₂ . After cooling to room temperature, the mixture was poured into water (150 ml) -dichloromethane (250 ml). The aqueous layer was extracted twice with 50 ml of dichloromethane and the combined organic layers were washed twice with 50 ml of water, dried over MgSO ₄ and concentrated in vacuo. The resulting crude product was purified by column chromatography (silica gel) using a mixture of dichloromethane: methanol (97: 3) as eluent. After concentration in vacuo, the pure product was obtained as a yellow oil (4.8 g, 13.8 mmol, 69% yield).

Step 2 (Scheme 3): A portion of Raney-Ni (Aldrich R 2800 [7440-02-0], ˜500 mg) was washed twice with 10 ml of 96% ethanol and then compound 11 ^* 4 under N ₂ . To an 8 g (13.8 mmol) solution (in 200 ml 96% ethanol). The solution was hydrated at room temperature and 1 atmosphere for 2.5 hours. The mixture was then filtered over Hyflo, washed with 300 ml of 96% ethanol, and the filtrate was concentrated in vacuo to give a quantitative yield of compound 12 ^* as a colored oil (4.36 g, 13.8 mmol, 100% yield). Gave.

Step 3 (Scheme 3): To a solution of compound 12 ^* (product from the previous step) 4.36 g (13.8 mmol) in 200 ml acetonitrile stirred at room temperature under nitrogen, 1,1 ′ -3.36 g (20.7 mmol) of carbonyldiimidazole (CDI, ACROS) was added. A precipitate that started to form after 10 minutes and increased to 3 hours was filtered off, washed with acetonitrile (200 ml) and dried in vacuo to give almost pure compound 13 ^* (3.30 g, 9.7 mmol, 70% Yield).

Step 4 (Scheme 3): Compound 13 ^* 3.30 g stirred under N ₂ and cooled to 0 ° C.
A portion of 1-chloroethyl chloroformate (1.17 ml, 10.7 mmol) was added dropwise to a suspension of (9.7 mmol) in 90 ml of 1,2-dichloroethane. After stirring for 30 minutes at 0 ° C. and 90 minutes at 80 ° C., the mixture was again cooled to 0 ° C. and another portion of 1-chloroethyl chloroformate (1.17 ml, 10.7 mmol) was added dropwise. The mixture was stirred again at 0 ° C. for 30 minutes and at 80 ° C. for 16 hours. After cooling to room temperature, the mixture was concentrated in vacuo and 75 ml of methanol was added to the residue. The resulting solution was stirred at 65 ° C. for 1 hour and concentrated under vacuum. After adding 75 ml of dichloromethane to the resulting brown semi-solid, it solidified under stirring for 1 hour. The precipitate was collected by filtration, washed with 100 ml of dichloromethane and dried. The resulting crude product was purified by column chromatography (silica gel) with a mixture of dichloromethane-methanol-ammonia (92: 7.5: 0.5) as eluent. After concentration under vacuum, compound 14 ^* was obtained as a white solid (1.61 g, 6.4 mmol, 66% yield).

Step 5 (Scheme 3): A mixture of compound 14 ^* 1.61 g (6.4 mmol) under N ₂ and 1.47 g (6.4 mmol) NO ₂ -imine (compound 7 ^* ) (200 ml of 1,2 In dichloroethane) and stirred at 50 ° C. for 16 h. After cooling to room temperature, 2.76 g (13 mmol) of NaBH (OAc) ₃ was added and the resulting mixture was stirred at room temperature under N ₂ for 24 hours. The slightly colored solution was poured onto a mixture of 300 ml dichloromethane, 100 ml water and 50 ml 5% aqueous NaHCO ₃ solution. The aqueous layer was washed twice with 70 ml dichloromethane and the combined organic layers were dried over MgSO ₄ and concentrated in vacuo. The crude product was purified by column chromatography (silica gel) with a mixture of dichloromethane: methanol: ammonia (92: 7.5: 0.5) as eluent. The pure product was concentrated under vacuum and then solidified upon co-evaporation with acetonitrile. After stirring in 100 ml di-isopropyl ether, the precipitate was filtered off and dried, Example 13 (1.35 g, as a slightly colored pure solid with M + of 422 m / z and melting point of 185-188 ° C. 3.2 mmol, 50% yield).

  The following specific examples were synthesized by these methods and comparable methods. They are intended to more specifically describe the present invention in more detail and are therefore not to be construed as limiting the scope of the invention in any way. Structural information for these compounds, all represented by general formula (1), is presented in the following table.

Pharmacological Assay The in vitro and in vivo ORL1 agonist properties of the compounds of the invention and their μ-opiate activity (lack of) were determined using the methods outlined below.

Affinity for human ORL1 receptor The affinity of a compound for human ORL1 receptor can be determined according to Ardati et al . , Mol. Pharmacol. , 51 , 816, 1997. Briefly, membrane preparations were obtained from CHO-cells in which the human ORL1 receptor is stably expressed. Membranes were incubated with [ ³ H] -nociceptin in the absence of test compound or in the presence of different concentrations of test compound diluted in an appropriate buffer. Non-specific binding was defined as binding remaining in the presence of 10 ⁻⁶ M nociceptin. Separation of the bound radioactivity from the educt was performed by filtration through a Packard GF / B glass fiber filter with several washes with ice-cold buffer using a Packard cell harvester. Bound radioactivity was measured with a scintillation counter (Topcount, Packard) using a liquid scintillation cocktail (Microscint 0, Packard). The measured radioactivity is plotted against the concentration of the displaceable test compound and the displacement curve is calculated by 4-parameter logistic regression to replace the IC ₅₀ value, ie 50% of the radioligand. Test compound concentrations. The affinity pK _i value is the Cheng-Prusoff equation:
pK _i = −log (IC ₅₀ / (1 + S / K _d ))
[Where IC ₅₀ is as described above, S is the [ ³ H] -nociceptin concentration (typically 0.2 nM) used in the assay expressed in mol / l, and Kd is the human ORL1 receptor [ ³ H] -nociceptin equilibrium dissociation constant (0.4 nM) for the body]
Calculated by correcting the IC ₅₀ value for the radioligand concentration and its affinity for the human ORL1 receptor.

  The compounds of the present invention have a high affinity for the ORL1 receptor in the binding assay described above. This property makes them useful in the treatment of disorders in which the ORL1 receptors are involved or can be treated by manipulation of these receptors.

Affinity for human μ-opiate receptor The affinity of a compound for μ-opiate receptor is described by Childers et al. , Eur. J. et. Determined using the in vitro receptor binding assay described by Pharm 55 , 11, 1979. Briefly, membrane preparations from CHO-cells in which the human μ-opiate receptor is stably expressed were obtained and diluted in the absence of the test compound or in an appropriate buffer, 10 μM to 0.1 nM. in the presence of a test compound in the concentration range of up to ^{[3 H]} - were incubated with naloxone. Non-specific binding was defined as binding remaining in the presence of 10 ⁻⁷ M levalorphan tartrate. Separation of bound radioactivity from educt is performed as described above, and compound affinity is similarly determined using a concentration of [ ³ H] -naloxone (S) of 1 nM and a K _d value of 1.3 nM. Calculated.

  Most compounds of the invention have a low affinity for the μ-opiate receptor in the binding assay described above. They are therefore unlikely to induce unwanted side effects known to occur with opiates such as morphine.

Activation of the ORL1 receptor agonist G protein-coupled ORL1 receptor in vitro inhibits adenylate cyclase activity and decreases the intracellular concentration of the second messenger cAMP. Jenck et al . , Proc. Naatl. Acad. Sci. USA, 97 , 4938-4943, 2000 was used to measure the activity of compounds against the ORL1 receptor. They have been shown to be potent agonists.

In Vivo ORL1 Receptor Agonism The compounds of the present invention can be administered after intraperitoneal and / or oral administration as described by Van der Poel et al., Psychopharmacology, 97 , 147-148, 1989, Conditioned Ultrasonic Distress Vocalization. It has been shown to be significantly effective in the (CUDV) method. This indicates that the compounds not only have good bioavailability after oral administration, but also pass through the “blood brain barrier”. The peptide nociceptin is also active in this assay, but to show its effect it needs to be administered directly into the brain (intracranial ventricular infusion).

An ORL1 agonist intravenously administered increasing amounts of the ORL1 agonist at 5-minute intervals to rats anesthetized with 80 mg / kg of intraperitoneal sodium pentobarbital that induced a decrease in blood pressure resulted in a decrease in blood pressure. This decrease ED _80: expressed as the dose, which results in a 20% reduction in blood pressure compared to control. In the interaction experiments, a single intravenous dose of the opiate antagonist naloxone 2 mg / kg or the selective ORL1 antagonist J- 113397 1 mg / kg was administered 10 minutes prior to the first dose of agonist. This dose of J-113397 was able to completely antagonize the effect of nociceptin. This dose of naloxone is known to antagonize the morphine-induced decrease in blood pressure, but had no effect on the nociceptin-induced decrease in blood pressure.

Effects of inducing ORL1 agonists and morphine on food intake Recent studies have shown that food intake can be pharmacologically regulated by opiate receptor ligands. Sanger and McCarthy (increased food and water intake brought to rats by opiate receptor agonists. Psychopahmalogy, 74 (3): 217-220, 1981) showed that systemic administration of morphine resulted in increased food intake and its effects Were shown to be reversible by the non-selective opiate antagonist naloxone. Further, Cicicociopo et al. (Synthetic nociceptin / orphan FQ receptor agonist, Ro 64-6198 improves stress- and CRF-induced anorexia in rats (reversal), Psychopahmalogy, 161 (2): 113-119, 2002) Reported that systemic administration of the ORL1 agonist Ro 64-6198 also increased food intake in rats.

  Male Wistar rats were placed in individual cages and given food and water ad libitum. Vehicle, Ro 64-6198 (1, 3, 6, 10 mg / kg), Example 1 (0.3, 1, 3, 6, 10 mg / kg) or morphine (1, 3, 10 mg / kg) intraperitoneally Once and the food was removed from the reach of the animals. 15 minutes after drug administration, a weighed amount of diet (5-6 pellets = 25-30 grams) was reintroduced into the animal cage. The diet was then reweighed after 60 and 120 minutes. All animals were reused for up to 4 separate experiments with a minimum of 5 days between experiments. Care was taken to ensure that external noise did not induce any further stress on the animals. In these experiments, the opiate antagonist naloxone (1, 3, 10 mg / kg) or the ORL1 antagonist J113397 (3, 10, 30 mg / kg) was used as the agonist (Ro 64-6198, 6 mg / kg, Example 1, 10 mg). / Kg or morphine 2 mg / kg) was administered prior to administration, and the antagonist was administered intraperitoneally 30 minutes prior to agonist administration. All experimental groups represented a minimum of 6 animals per group.

Preparation of compounds used in animal studies Preparation of Example 1:
For oral (po) administration : To a desired amount (0.5-15 mg) of Example 1 solid in a glass tube, add some glass beads and vortex the solid for 2 minutes By grinding. After the addition of 1 ml of a 1% methylcellulose solution in water, the compound was suspended by vortexing for 10 minutes. In order to concentrate to 1 mg / 1 ml or more, the remaining particles in the suspension were further suspended by using an ultrasonic bath.

For intraperitoneal (ip) administration : To a desired amount (0.5-15 mg) of Example 1 solid in a glass tube, add some glass beads and vortex the solid for 2 minutes And then pulverized. After addition of 1 ml of 1% methylcellulose and 5% mannitol solution (in water), the compound was suspended by vortexing for 10 minutes. Finally, the pH was adjusted to 7.

Preparation of Example 2:
For oral (po) administration : To a desired dose (0.5-15 mg) of Example 2 solid in a glass tube, add some glass beads and vortex the solid for 2 minutes By grinding. After addition of 1 ml of 1% aqueous methylcellulose, the compound was suspended by vortexing for 10 minutes. The pH was adjusted to 7 with a few drops of aqueous NaOH (0.1N). The remaining particles in the suspension were further suspended by using an ultrasonic bath.

For intraperitoneal (ip) administration : The preparations were administered p.p. by using 1% methylcellulose and 5% mannitol instead of 1% methylcellulose (in water). o. Obtained similar to that used for administration.

  From the data in the table above, it is clear that Example 1 is 10 times more potent than Ro 64-6198 when administered by the intraperitoneal route and 3 times more potent when administered orally.

  The above data shows that the blood pressure lowering effect of Example 1 (range 10-3000 μg / kg) was antagonized by J-113397 (dose-response shift of 356-1138 μg / kg), but the effect is sensitive with naloxone (No shift in dose-response at 356 and 334 μg / kg). The effect of Ro 64-6198 (range 10-1000 μg / kg) was antagonized by J-113397 (84-264 μg / kg dose response shift) and the effect at the two highest doses was sensitive to naloxone (84-141 μg / kg dose response shift). Ro 64-6198 clearly has a μ-opiate component.

Morphine (1.25, 2.5, 5 and 10 mg / kg), Ro 64-6198 (1, 3 and 10 mg / kg ip) and Example 1 (0.3, 1, 3, 6, 10 mg / kg) , Intraperitoneal) all resulted in a dose-dependent increase in food intake, which was significant for the vehicle treated group in all cases. The systemic administration of the opiate antagonist naloxone (3 or 30 mg / kg ip) alone and the ORL1 antagonist J113397 (30 mg / kg ip) alone had no effect on food intake.

  Increased food intake after morphine administration was antagonized in the presence of the opiate receptor antagonist naloxone. The increase in food intake associated with Example 1 was completely antagonized by the ORL1 antagonist J113397, but not by the opiate receptor antagonist naloxone. J1133337 did not antagonize the increased food intake associated with Ro 64-6198 (statistically significant), whereas pretreatment with naloxone resulted in a significant reversal of Ro 64-6198 induction of food intake. .

  This data suggests that the increased food intake associated with Example 1 is mediated by agonism at the ORL1 receptor and not by the opiate receptor. The increase in food intake associated with Ro 64-6198 was partially antagonized by naloxone, but not by J113397, in contrast to Ro 64-6198 there is an opium component that is not present in Example 1. Suggests that. In conclusion, Example 1 acts as a more selective ORL1 agonist compared to Ro 64-6198.

Claims (9)

General formula (1)

[Where:
R ₁ represents H, alkyl (1-6C), alkyl (1-3C) cycloalkyl (3-6C), carboalkoxy (2-7C) or acyl (2-7C);
_{[] M} is - _{(CH 2) m} - represents, wherein m is either 0 or 1,
R ₂ is halogen, CF ₃ , alkyl (1-6C), alkyl (1-3C) cycloalkyl (3-6C), phenyl, amino, aminoalkyl (1-3C), alkyl (1-3C) amino, dialkyl (1-3C) amino, cyano, cyanoalkyl (1-3C), hydroxy, hydroxyalkyl (1-3C), (1-3C) alkoxy, OCF ₃ , acyl (2-7C), trifluoroacetyl, aminocarboxyl , (1-3C) alkylsulfonyl or trifluoromethylsulfonyl, and n is an integer of 0 to 4, provided that when n is 2, 3 or 4, the R ₂ substituents are the same Or it may be different,
A is a saturated or partially unsaturated ring;
_{[] O} and _{[] p} are each - _{(CH 2) o} - and - _{(CH 2) p} - and represents, wherein A is a ring of partially unsaturated, and o and p are independently 0, 1 or The meaning of -CH- is also possible when
R ₃ , R ₄ , R ₅ and R ₆ independently represent hydrogen, alkyl (1-3C), alkyl (1-3C) cycloalkyl (3-6C), CH ₂ OH or (R ₃ and R ₅ ) Or (R ₃ and R ₆ ) or (R ₄ and R ₅ ) or (R ₄ and R ₆ ) can form together an alkylene bridge of 1 to 3 carbon atoms, provided that o When is 2, R ₃ is hydrogen, and when p is 2, R ₅ is hydrogen;
R ₇ is H, halogen, CF ₃ , alkyl (1-6C), alkyl (1-3C) cycloalkyl (3-6C), amino, aminoalkyl (1-3C), alkyl (1-3C) amino, dialkyl (1-3C) represents amino, hydroxy, hydroxyalkyl (1-3C), (1-3C) alkoxy, OCF3, acyl (2-7C), aminocarboxyl or (1-3C) alkylsulfonyl]
Compounds, all stereoisomers and pharmacologically acceptable salts and groups which are easily removed after administration, eg amidine, enamine, Mannich base, hydroxyl-methylene derivatives, O- (acyloxymethylene carbamate) A prodrug which is a derivative of a compound having formula (1) in the presence of a derivative, carbamate or enaminone. A is a saturated ring, R ₁ represents hydrogen, alkyl (1-3C) or acyl (2-4C), R ₃ , R ₄ , R ₅ and R ₆ are independently hydrogen, alkyl (1-3C) Or (R ₃ and R ₅ ) or (R ₃ and R ₆ ) or (R ₄ and R ₅ ) or (R ₄ and R ₆ ) together with an alkylene bridge of 1 to 3 carbon atoms Provided that when o is 2, R ₃ is hydrogen and when p is 2, R ₅ is hydrogen and R ₇ is H, halogen, CF ₃ , Alkyl (1-3C), amino, aminoalkyl (1-3C), alkyl (1-3C) amino, dialkyl (1-3C) -amino, hydroxy, (1-3C)
An alkoxy or OCF _3, and _R 2, m, n, the general formula of claim 1 having the meanings o and p are shown in the compound (1). A is a saturated ring, m = 0, n = 0 or 1, o = 1, p = 1, R ₁ = H or acetyl, R ₂ is halogen, CF ₃ , alkyl (1-3C), amino , Cyano, OCH ₃ or OCF ₃ , R ₃ , R ₄ , R ₅ and R ₆ independently represent hydrogen or alkyl (1-2C) or (R ₄ and R ₆ ) together 1 The general formula according to claim 1, wherein an alkylene bridge of ~ 2 carbon atoms can be formed and R ₇ represents H, halogen, CF ₃ , alkyl (1-3C), amino, hydroxy or OCF _3. Compound (1). Formula (2)

The compound according to claim 1 having the formula and stereoisomers thereof. R ₇ is useful for the synthesis of compounds having general formula (1), and R ₇ has the meaning indicated in claim 1

Compound.   The compound or a salt thereof according to any one of claims 1 to 4, for use as a medicament.   A pharmaceutical composition comprising a pharmacologically effective amount of at least one compound according to any one of claims 1 to 4 as an active ingredient.   A compound according to any one of claims 1 to 4 for the preparation of a pharmaceutical composition for the treatment of disorders in which ORL1 receptors are involved or can be treated by manipulation of these receptors. use. Said disorders are acute and chronic pain conditions, central nervous system disorders, in particular, but not limited to, improvement of symptoms of anxiety and stress disorders, depression, various forms of epilepsy, stroke, cognitive and memory deficits Disorders characterized by, for example, Alzheimer's disease, Kreutzert-Jakob disease, Huntington's disease, Parkinson's disease, neurological rehabilitation (posttraumatic brain injury); acute brain or spinal cord injury (such as addiction and abuse) Substance-related disorders including substance use disorders and substance-induced disorders (such as substance withdrawal symptoms); eating disorders such as anorexia nervosa and bulimia nervosa, obesity; gastrointestinal disorders, especially irritable bowel syndrome, inflammation Kidney disease characterized by inflammatory bowel disease (Crohn's disease) and ulcerative colitis, urinary tract inflammation, water retention / excretion or salt excretion; cardiovascular disorders such as heart Infarction, arrhythmias, hypertension, thrombosis, anemia, arteriosclerosis, angina, skin disorders, for example, urticaria, lupus erythematosus and pruritus; ophthalmic disorders such as glaucoma;
Use according to claim 8, characterized by respiratory disorders including chronic obstructive pulmonary artery disease, bronchitis and cystic fibrosis; diseases of the immune system, and viral infections.